The I-O Quest

Exploring the research behind why some people respond to immunotherapy and others do not

2017/06/02

I

mmuno-Oncology (I-O), and the research behind it, aspires to beat cancer at its own game. In February 2017, it was named advance of the year for a second year in a row by the American Society of Clinical Oncology (ASCO). “The sheer amount of translational research underway with groundbreaking I-O approaches is very exciting,” says Steven Averbuch, vice president, Translational Clinical Development & Pharmacodiagnostics at Bristol-Myers Squibb.

But despite the progress to date, less than 50 percent of patients respond to I-O, depending on the patient population and the specific types of cancers involved. A stat like that begs the question: Why do some people respond to immunotherapies while others don’t?

Building on knowledge gleaned from nearly 20 years of researching immunotherapies, Bristol-Myers Squibb scientists are hunting for answers to that question at an accelerated pace with the help of cutting-edge technologies. They are investigating the biology of cancer and the immune system at the cellular level, analyzing massive amounts of genomic data from tumor databanks and clinical trials, and using biomarkers and companion diagnostics to guide faster decision-making.

Nils Lonberg

From biologic discovery to translational science, Bristol-Myers Squibb’s I-O experts are engaged in a relentless pursuit to discover, develop, and design the next generation of immunotherapies.

Hunting Promising Targets

The hunt starts by learning as much as possible about the biology of cancer and the human immune system. Nils Lonberg, senior vice president of Oncology Biology Discovery, says three biological mechanisms affect cancer’s ability to evade detection and grow out of control:

Cancer cells have mutations that may or may not be expressed. Cancer cells are fickle. They might make neoantigens, proteins on their cell surfaces, that enable immune cells to detect their presence and target them for destruction, or they might not. Not to mention, the total number of mutations varies among cancer types. Childhood leukemias, for example, are driven by a limited set of mutations that can be well controlled with targeted therapies. Most cancers, though, have many mutations that make them hard to target, thus allowing them to grow out of control.

The balance of the body’s inflammatory response is disrupted. In a healthy inflammatory response, immune cells respond to signals by rushing in to deal with a problem, causing inflammation and swelling—like when you cut your finger and it becomes red and swollen. When the threat is over, other signals tell the inflammatory response to end so that the wound can heal. A healthy body maintains a proper balance in both directions of the inflammatory pathways. Tumors, however, are stuck at a particular point in this cycle where inflammatory attenuation signals have shut down a productive T-cell response before the cancer cells have been cleared.

Cancer cells are always mutating. Like bacteria, cancer cells are under tremendous molecular pressure, rapidly dividing and mutating all the time. New mutations can equip cancer cells with other ways to escape attack from immune cells, such as blocking infiltration, masking themselves from detection, or developing resistance to earlier therapies by expressing different surface proteins.

As a means of identifying the most promising targets to pursue, scientists look for the specific protein receptors on the surfaces of immune cells that are involved with those biological mechanisms. Bristol-Myers Squibb is researching dozens of targets at various stages of investigation.

“

"The sheer amount of translational research underway with groundbreaking I-O approaches is very exciting." -Steven Averbuch

”

Tim Reilly

“We follow the science as much as we can, taking all the input around a potential target by studying the disease, conducting animal studies, looking at translational data, and then forming hypotheses to test and see what happens,” says Tim Reilly, vice president and head of Early Oncology. “We also include the ability to learn why something worked or didn’t work, no matter the outcome. Understanding why something doesn’t work is often just as important as understanding why it did.”

Bruce Car

That input-gathering process includes reviewing published literature, scouring The Cancer Genome Atlas—a large public database that has multidimensional diagrams of genomic mutations in 33 types of cancer—and analyzing genomic datasets from patients in clinical trials. “We look for targets that are highly expressed in tumor types that have a higher incidence and a higher medical need,” says Bruce Car, vice president and head of Translational Sciences.

David Feltquate

Evaluating Clinical Research Data

Bristol-Myers Squibb is currently studying many molecules specifically engineered to target different immune system pathways in a variety of cancer types.

“We adapt our drug development program based on what we learn, and it’s an iterative process,” says David Feltquate, head of Oncology Early Clinical Development. “With the tools at our disposal today, we aim to identify patients who are more likely to respond, by specific characteristics, much earlier in the research process. Those characteristics inform and enrich our whole program. And we don’t give up on the patients who are less likely to respond; we might be able to give them another drug.”

In addition to collecting standard clinical trial data, such as safety information and response rates, Bristol-Myers Squibb scientists are pioneering new ways to inform the best insights as early as possible.

“

"We are actively engaging commercial partners who have biomarker and companion diagnostic expertise to ensure we are bringing the right drugs to the right patients." -Anil Kapur

”

Anil Kapur

"We are actively engaging commercial partners who have diagnostic expertise and a global market reach to ensure that we are delivering the best customer experience and bringing the right drugs to the right patients," says Anil Kapur, vice president, I-O Early Assets & Biomarkers Commercialization. Biomarkers can be used to characterize a tumor and the tumor microenvironment, which may inform how a patient might respond to immunotherapy. Companion diagnostics are used to identify patients who will benefit from an available treatment.

Learn More: The role of immune biomarkers in the tumor microenvironment

The company’s scientists are also using advanced imaging technologies to examine the biology of immune response processes at the millimolecular level (one-thousandth of a molecule), which allows them to see more precisely how cancer responds. "We are in the early stages of developing imaging agents that help us use PET imaging (positron emission tomography) to visualize interesting biology in patients," Feltquate says.

Steven Averbuch

Pursuing Next Generation I-O Research

The next generation of I-O research is already underway across the sector. With it has come an exciting shift in approach to investigate combination treatments that may be able to address more than one cancer target at the same time.

“If cancer is like a room that has multiple lights turned on, standard chemotherapy is like breaking all the lights at once to turn them off,” says Steven Averbuch. “Targeted therapy, using a targeted drug to treat a cancer largely driven by a single mutation, is akin to turning off a switch that controls most of the lights in the room. In our current era of immuno-oncology, we are researching a whole bank of light switches that we hope to one day be able to turn off in different sequences and combinations along the patient journey.”

Furthermore, a growing number of industry collaborations with biotech firms and academic research centers will allow Bristol-Myers Squibb to leverage new understandings about the nature of cancer, and find new ways to use informatics and other tools to apply data in a way that wasn’t possible in the past.

“We’re getting closer to knowing why some people respond to I-O and others don’t,” Averbuch says. “Our goal is to keep going in hopes that we can potentially turn out the lights on cancer for good.”